US5229526A - Metal alkoxides - Google Patents
Metal alkoxides Download PDFInfo
- Publication number
- US5229526A US5229526A US07/862,778 US86277892A US5229526A US 5229526 A US5229526 A US 5229526A US 86277892 A US86277892 A US 86277892A US 5229526 A US5229526 A US 5229526A
- Authority
- US
- United States
- Prior art keywords
- solution
- taxol
- mixture
- triethylsilyl
- thf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 40
- 239000002184 metal Substances 0.000 title claims abstract description 40
- 150000004703 alkoxides Chemical class 0.000 title claims abstract description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000006239 protecting group Chemical group 0.000 claims abstract description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 14
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 7
- 150000003624 transition metals Chemical class 0.000 claims abstract description 7
- -1 1-ethoxyethyl Chemical group 0.000 claims description 31
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910052719 titanium Inorganic materials 0.000 claims description 4
- 229910052768 actinide Inorganic materials 0.000 claims description 2
- 150000001255 actinides Chemical class 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims 1
- 125000005106 triarylsilyl group Chemical group 0.000 claims 1
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 abstract description 24
- 238000002360 preparation method Methods 0.000 abstract description 23
- 150000004200 baccatin III derivatives Chemical class 0.000 abstract description 11
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 141
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 112
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 239000000203 mixture Substances 0.000 description 79
- 229930012538 Paclitaxel Natural products 0.000 description 74
- 229960001592 paclitaxel Drugs 0.000 description 72
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 67
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 64
- 125000003118 aryl group Chemical group 0.000 description 61
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 56
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 32
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 31
- 238000001704 evaporation Methods 0.000 description 30
- 230000008020 evaporation Effects 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 229930014667 baccatin III Natural products 0.000 description 24
- 150000003952 β-lactams Chemical class 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 17
- 239000000463 material Substances 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 9
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229940063683 taxotere Drugs 0.000 description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 6
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 150000002902 organometallic compounds Chemical class 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 229940123237 Taxane Drugs 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 125000006242 amine protecting group Chemical group 0.000 description 4
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 4
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 150000004579 taxol derivatives Chemical class 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 241000202349 Taxus brevifolia Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- 239000000039 congener Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SKJSIVQEPKBFTJ-HUWILPJBSA-N taxusin Chemical compound C1[C@@H](C2(C)C)C[C@H](OC(C)=O)C(C)=C2[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@]2(C)CC[C@H](OC(=O)C)C(=C)[C@@H]12 SKJSIVQEPKBFTJ-HUWILPJBSA-N 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- XSYLUBKWRZCOQP-QIWLAUOQSA-N (3s,4r)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1([C@@H]([C@@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 XSYLUBKWRZCOQP-QIWLAUOQSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- 229930182986 10-Deacetyltaxol Natural products 0.000 description 1
- QPLJYAKLSCXZSF-UHFFFAOYSA-N 2,2,2-trichloroethyl carbamate Chemical compound NC(=O)OCC(Cl)(Cl)Cl QPLJYAKLSCXZSF-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- LUYQINUDJUXWNB-UHFFFAOYSA-N 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1C(=O)C(OC(C)OCC)C1C1=CC=CC=C1 LUYQINUDJUXWNB-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 101100177155 Arabidopsis thaliana HAC1 gene Proteins 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101100434170 Oryza sativa subsp. japonica ACR2.1 gene Proteins 0.000 description 1
- 101100434171 Oryza sativa subsp. japonica ACR2.2 gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000005104 aryl silyl group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- LBIYGLHRYUODBK-UHFFFAOYSA-N ethyl 2-triethylsilyloxyacetate Chemical compound CCOC(=O)CO[Si](CC)(CC)CC LBIYGLHRYUODBK-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- PKMBLJNMKINMSK-UHFFFAOYSA-N magnesium;azanide Chemical group [NH2-].[NH2-].[Mg+2] PKMBLJNMKINMSK-UHFFFAOYSA-N 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical group [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical group [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000005911 methyl carbonate group Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002900 organolithium compounds Chemical group 0.000 description 1
- 150000002901 organomagnesium compounds Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AWQUYUAEGSCHBU-UHFFFAOYSA-N tert-butyl n-chlorocarbamate Chemical compound CC(C)(C)OC(=O)NCl AWQUYUAEGSCHBU-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention is directed to novel metal alkoxides useful in the preparation of derivatives of baccatin III and 10-deacetyl baccatin III such as taxol, taxotere and other taxane derivatives which have biological activity.
- Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has the following structure: ##STR2## Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States.
- Taxus brevifolia (Western Yew).
- taxol is found only in minute quantities in the bark of these slow growing evergreens, causing considerable concern that the limited supply of taxol will not meet the demand. Consequently, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxols. So far, the results have not been entirely satisfactory.
- 10-deacetyl baccatin III is converted to taxol by attachment of the C-10 acetyl group and by attachment of the C-13 ⁇ -amido ester side chain through the esterification of the C-13 alcohol with a ⁇ -amido carboxylic acid unit.
- this approach requires relatively few steps, the synthesis of the ⁇ -amido carboxylic acid unit is a multi-step process which proceeds in low yield, and the coupling reaction is tedious and also proceeds in low yield.
- this coupling reaction is a key step which is required in every contemplated synthesis of taxol or biologically active derivative of taxol, since it has been shown by Wani, et al. in JACS 93, 2325 (1971) that the presence of the ⁇ -amido ester side chain at C13 is required for anti-tumor activity.
- taxol derivatives of the formula III below have an activity significantly greater than that of taxol (I).
- R' represents hydrogen or acetyl and one of R" and R'" represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof.
- Denis et al. disclose a different process for preparing derivatives of baccatin III or of 10-deactylbaccatin III of general formula ##STR6## in which R' denotes hydrogen or acetyl wherein an acid of general formula: ##STR7## in which R 1 is a hydroxy-protecting group, is condensed with a taxane derivative of general formula: ##STR8## in which R 2 is an acetyl hydroxy-protecting group and R 3 is a hydroxy-protecting group, and the protecting groups R 1 , R 3 and, where appropriate, R 2 are then replaced by hydrogen.
- this method employs relatively harsh conditions, proceeds with poor conversion, and provides less than optimal yields.
- a major difficulty remaining in the synthesis of taxol and other potential anti-tumor agents is the lack of baccatin III and 10-deacetyl baccatin III derivatives which have been activated at the C-13 oxygen. Development of such derivatives would permit attachment of the ⁇ -amido ester side chain in high yield and thus, facilitate the synthesis of taxol as well as related anti-tumor agents having a modified set of nuclear substituents or a modified C-13 side chain.
- the present invention is directed to a metal alkoxide having the formula: ##STR9## wherein T 1 is hydrogen or a hydroxy protecting group, Z is --OT 2 , or --OCOCH 3 , T 2 is hydrogen or a hydroxy protecting group, and M is a metal, preferably, Li, Mg, Na, K or Ti.
- Metal alkoxides (1) are activated derivatives of baccatin III and/or 10-deacetyl baccatin III and have particular utility in a process for the preparation of taxol, taxotere and other biologically active taxane derivatives.
- metal alkoxides (1) are reacted with ⁇ -lactam (2) to form a ⁇ -amido ester intermediate. The intermediate is then converted to a biologically active taxane derivative.
- ⁇ -lactam (2) has the general formula: ##STR10## wherein R 1 is --OR 6 , --SR 7 , or --NR 8 R 9 ;
- R 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl
- R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or acyl, provided, however, that R 3 and R 4 are not both acyl;
- R 5 is --COR 10 , --COOR 10 , --COSR 10 , --CONR 8 R 10 , --SO 2 R 11 , or --POR 12 R 13 ;
- R 6 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group
- R 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group
- R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl
- R 9 is an amino protecting group
- R 10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
- R 11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ;
- R 12 and R 13 are independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, --OR 10 , or --NR 8 R 14 ;
- R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
- R 5 of ⁇ -lactam (2) is preferably --COR 10 with R 10 being aryl, p-substituted phenyl, or lower alkoxy, and most preferably, phenyl, methoxy, ethoxy, tert-butoxy ("tBuO"; (CH 3 ) 3 CO--) or ##STR11## wherein X is Cl, Br, F, CH 3 O--, or NO 2 --.
- R 2 and R 4 are hydrogen or lower alkyl.
- R 3 is preferably aryl, most preferably, naphthyl, phenyl, ##STR12## wherein X is as previously defined, Me is methyl and Ph is phenyl.
- R 1 is selected from --OR 6 , --SR 7 or --NR 8 R 9 wherein R 6 , R 7 and R 9 , are hydroxy, sulfhydryl, and amine protecting groups, respectively, and R 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
- R 1 is --OR 6 wherein R 6 is triethylsilyl ("TES"), 1-ethoxyethyl (“EE”) or 2,2,2-trichloroethoxymethyl.
- the ⁇ -lactam alkyl groups are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, aryl, hexyl, and the like.
- the ⁇ -lactam alkenyl groups are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, aryl, hexenyl, and the like.
- the ⁇ -lactam alkynyl groups are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, aryl, hexynyl, and the like.
- ⁇ -lactam aryl moieties described contain from 6 to 15 carbon atoms and include phenyl, ⁇ -naphthyl or ⁇ -naphthyl, etc.
- Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
- R 1 of ⁇ -lactam (2) may be -OR 6 with R 6 being alkyl, acyl, ethoxyethyl ("EE"), triethylsilyl ("TES”), 2,2,2-trichloroethoxymethyl, or other hydroxyl protecting group such as acetals and ethers, i.e., methoxymethyl (“MOM”), benzyloxymethyl; esters, such as acetates; carbonates, such as methyl carbonates; and alkyl and aryl silyl such as triethylsilyl, trimethylsilyl, dimethyl-t-butylsilyl, dimethylarylsilyl, dimethylheteroarylsilyl, and triisopropylsilyl, and the like.
- R 6 being alkyl, acyl, ethoxyethyl (“EE”), triethylsilyl ("TES”), 2,2,2-trichloroethoxymethyl, or other hydroxyl protecting group
- hydroxyl protecting group for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981.
- the hydroxyl protecting group selected should be easily removed under conditions that are sufficiently mild, e.g., in 48% HF, acetonitrile, pyridine, or 0.5% HCl/water/ethanol, and/or zinc, acetic acid so as not to disturb the ester linkage or other substituents of the taxol intermediate.
- R 7 may be a sulfhydryl protecting group and R 9 may be an amine protecting group.
- Sulfhydryl protecting groups include hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates.
- Amine protecting groups include carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate.
- a variety of sulfhydryl and amine protecting groups may be found in the above-identified text by T. W. Greene.
- ⁇ -lactams (2) can be prepared from readily available materials, as is illustrated in schemes A and B below: ##STR13## reagents: (a) triethylamine, CH 2 Cl 2 , 25° C., 18 h; (b) 4 equiv ceric ammonium nitrate, CH 3 CN, -10° C., 10 min; (c) KOH, THF, H 2 O, 0° C., 30 min; (d) ethyl vinyl ether, THF, toluene sulfonic acid (cat.), 0° C., 1.5 h; (e) n-butyllithium, ether, -78° C., 10 min; benzoyl chloride, -78° C., 1 h; (f) lithium diisopropyl amide, THF -78° C. to -50° C.; (g) lithium hexamethyldisilazide, THF -78° C. to 0°
- ⁇ -Acyloxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones.
- the p-methoxyphenyl group can be readily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones.
- the 3-hydroxyl group is protected with 1-ethoxyethyl, but may be protected with variety of standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups.
- ethyl- ⁇ -triethylsilyloxyacetate is readily prepared from glycolic acid.
- racemic ⁇ -lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters.
- the reaction described hereinbelow in which the ⁇ -amido ester side chain is attached has the advantage of being highly diastereoselective, thus permitting the use of a racemic mixture of side chain precursor.
- the 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one of Scheme A and the 3-(1-triethylsilyl)-4-phenylazetidin-2-one of Scheme B can be converted to ⁇ -lactam (2), by treatment with a base, preferably n-butyllithium, and an acyl chloride, sulfonyl chloride, phosphinyl chloride, phosphoryl chloride or an alkyl chloroformate at -78° C. or less.
- the metal alkoxides are prepared by reacting an alcohol having two to four rings of the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent.
- the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al. in JACS 110, 5917 (1988) or by other routes) or 7,10-bis-O-triethylsilyl baccatin III.
- 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme: ##STR14## Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C 2 H 5 ) 3 SiCl at 23° C. under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl baccatin III to provide 7-triethylsilyl-10-deacetyl baccatin III (4a) as a reaction product in 84-86% yield after purification.
- reaction product (4a) is then acetylated with 5 equivalents of CH 3 COCl and 25 mL of pyridine/mmol of 4a at 0° C. under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (4b) as reported by Greene, et al. in JACS 110, 5917 at 5918 (1988).
- 7-triethylsilyl-10-deacetyl baccatin III (4a) can be protected at C-10 oxygen with an acid labile hydroxyl protecting group.
- treatment of (4a) with n-butyllithium in THF followed by triethylsilyl chloride (1.1 mol equiv.) at 0° C. gives 7,10-bis-O-triethylsilyl baccatin III (4c) in 95% yield.
- (4a) can be converted to 7-O-treithylsilyl-10-(1-ethoxyethyl) baccatin III (4d) in 90% yield by treatment with excess ethyl vinyl ether and a catalytic amount of methane sulfonic acid.
- the 7-O-triethylsilyl baccatin III derivatives (4b, 4c or 4d) are reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III derivative (5b, 5c or 5d) as shown in the following reaction scheme: ##STR16##
- the 13-O-lithium-7-O-triethylsilyl baccatin III derivative (b, 5c, or 5d) reacts with ⁇ -lactam (2) to provide an intermediate (6b, 6c, or 6d) in which the C-7 and C-2' hydroxyl groups are protected with a triethylsilyl group.
- the triethylsilyl and ethoxyethyl groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents.
- the 7-O-triethylsilyl baccatin III derivatives (4b, 4c or 4d) are reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III derivative (5b, 5c or 5d) as shown in the following reaction scheme: ##STR17##
- the 13-O-lithium-7-O-triethylsilyl baccatin III derivative (b, 5c, or 5d) reacts with ⁇ -lactam (2) to provide an intermediate (6b, 6c, or 6d) in which the C-7 and C-2' hydroxyl groups are protected with a triethylsilyl group.
- the triethylsilyl and ethoxyethyl groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents.
- T 1 is a hydroxy protecting group
- M is a metal
- Ph is phenyl
- Ac is acetyl
- R 1 to R 5 are as previously defined.
- Metal substituent, M, of metal alkoxide (3) is a Group IA, IIA, IIIA, lanthanide or actinide element or a transition, Group IIIA, IVA, VA or VIA metal.
- it is a Group IA, IIA or transition metal, and most preferably, it is lithium, magnesium, sodium, potassium or titanium.
- Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel.
- the ⁇ -lactam is added to the reaction vessel after formation therein of the metal alkoxide.
- the organometallic compound n-butyllithium is preferably used to convert baccatin III or 10-deacetyl baccatin III to the corresponding metal alkoxide, but other sources of metallic substituent such as lithium diisopropyl amide, other lithium or magnesium amides, ethylmagnesium bromide, methylmagnesium bromide, other organolithium compounds, other organomagnesium compounds, organosodium, organotitanium or organopotassium may also be used.
- Organometallic compounds are readily available, or may be prepared by available methods including reduction of organic halides with metal. For example, butyl bromide can be reacted with lithium metal in diethyl ether to give a solution of n-butyllithium in the following manner: ##STR19##
- THF is the preferred solvent for the reaction mixture
- other ethereal solvents such as dimethoxyethane, or aromatic solvents may also be suitable.
- Other solvents are not appropriate for other reasons. For example, esters are not appropriate for use with certain organometallic compounds such as n-butyllithium due to incompatibility therewith.
- the reaction scheme disclosed herein is ideally directed to the synthesis of taxol, taxotere, and other taxane derivatives exemplified herein, it can be used with modifications in either the ⁇ -lactam or the tetracyclic metal alkoxide to produce other compounds.
- the ⁇ -lactam and the tetracyclic metal alkoxide can be derived from natural or unnatural sources, to prepare other synthetic taxols, taxol derivatives, 10-deacetyltaxols, and the enantiomers and diastereomers thereof contemplated within the present invention.
- the process of the invention also has the important advantage of being highly diastereoselective. Therefore racemic mixtures of the side chain precursors may be used. Substantial cost savings may be realized because there is no need to resolve racemic ⁇ -lactams into their pure enantiomers. Additional cost savings may be realized because less side chain precursor, e.g., 60-70% less, is required relative to prior processes.
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- Chemical & Material Sciences (AREA)
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- Epoxy Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Silicates, Zeolites, And Molecular Sieves (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
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Priority Applications (32)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/862,778 US5229526A (en) | 1991-09-23 | 1992-04-03 | Metal alkoxides |
IL103192A IL103192A (en) | 1991-09-23 | 1992-09-16 | Metal alkoxides |
PH44959A PH30213A (en) | 1991-09-23 | 1992-09-21 | Metal alkoxides |
PT100884A PT100884B (pt) | 1991-09-23 | 1992-09-21 | Alcoxidos de metal uteis na preparacao de derivados taxano |
MYPI92001683A MY128481A (en) | 1991-09-23 | 1992-09-21 | Semi-synthesis of taxane derivatives using metal alkoxides and beta-lactams. |
MX9205370A MX9205370A (es) | 1991-09-23 | 1992-09-22 | Alcoxidos metalicos. |
SG1996005624A SG63594A1 (en) | 1991-09-23 | 1992-09-22 | Metal alkoxides |
UA94005359A UA41287C2 (uk) | 1991-09-23 | 1992-09-22 | Алкоголяти металів для отримання похідних таксану |
ES92921317T ES2137951T3 (es) | 1991-09-23 | 1992-09-22 | Alcoxidos de metales. |
DE69229916T DE69229916T2 (de) | 1991-09-23 | 1992-09-22 | Metallalkoxide |
EP92921317A EP0605638B1 (fr) | 1991-09-23 | 1992-09-22 | Alcoxydes de metaux |
RU9494019168A RU2098413C1 (ru) | 1991-09-23 | 1992-09-22 | Алкоголяты металлов |
PCT/US1992/007952 WO1993006094A1 (fr) | 1991-09-23 | 1992-09-22 | Alcoxydes de metaux |
DK92921317T DK0605638T3 (da) | 1991-09-23 | 1992-09-22 | Metalalkoxider |
CZ1994662A CZ289299B6 (cs) | 1991-09-23 | 1992-09-22 | Alkoxidy kovů |
JP50627793A JP3320416B2 (ja) | 1991-09-23 | 1992-09-22 | 金属アルコキシド |
CA002098568A CA2098568C (fr) | 1991-09-23 | 1992-09-22 | Alcoxydes de metal |
US07/949,066 US5274124A (en) | 1991-09-23 | 1992-09-22 | Metal alkoxides |
AU26888/92A AU643911B2 (en) | 1991-09-23 | 1992-09-22 | Metal alkoxides |
AT92921317T ATE184004T1 (de) | 1991-09-23 | 1992-09-22 | Metallalkoxide |
HU9400831A HU225914B1 (en) | 1991-09-23 | 1992-09-22 | Process for producing of new metal alkoxides |
CN92112482A CN1058714C (zh) | 1991-09-23 | 1992-09-23 | 金属醇盐的制备方法 |
NZ244458A NZ244458A (en) | 1991-09-23 | 1992-09-23 | Metal alkoxides of taxane derivatives |
TW081108376A TW368502B (en) | 1991-09-23 | 1992-10-21 | Metal alkoxides |
US08/034,247 US5430160A (en) | 1991-09-23 | 1993-03-22 | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
EG18993A EG20320A (en) | 1992-04-03 | 1993-03-30 | Process for preparing of metal alkoxides |
NO941020A NO305120B1 (no) | 1991-09-23 | 1994-03-22 | Metallalkoksider |
FI941323A FI109796B (fi) | 1991-09-23 | 1994-03-22 | Metallialkoksidit |
US08/476,357 US5717115A (en) | 1991-09-23 | 1995-06-07 | Metal alkoxides and ammonium alkoxides |
GR990402796T GR3031704T3 (en) | 1991-09-23 | 1999-11-03 | Metal alkoxides. |
US09/516,870 US6458977B1 (en) | 1991-09-23 | 2000-03-02 | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US09/566,970 US6495704B1 (en) | 1991-09-23 | 2000-05-09 | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US76380591A | 1991-09-23 | 1991-09-23 | |
US07/862,778 US5229526A (en) | 1991-09-23 | 1992-04-03 | Metal alkoxides |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US76380591A Continuation-In-Part | 1991-09-23 | 1991-09-23 |
Related Child Applications (4)
Application Number | Title | Priority Date | Filing Date |
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US76380591A Continuation-In-Part | 1991-09-23 | 1991-09-23 | |
US07/949,066 Continuation-In-Part US5274124A (en) | 1991-09-23 | 1992-09-22 | Metal alkoxides |
US08/034,247 Continuation-In-Part US5430160A (en) | 1991-09-23 | 1993-03-22 | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US08/476,357 Continuation-In-Part US5717115A (en) | 1991-09-23 | 1995-06-07 | Metal alkoxides and ammonium alkoxides |
Publications (1)
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US5229526A true US5229526A (en) | 1993-07-20 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US07/862,778 Expired - Lifetime US5229526A (en) | 1991-09-23 | 1992-04-03 | Metal alkoxides |
Country Status (24)
Country | Link |
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US (1) | US5229526A (fr) |
EP (1) | EP0605638B1 (fr) |
JP (1) | JP3320416B2 (fr) |
CN (1) | CN1058714C (fr) |
AT (1) | ATE184004T1 (fr) |
AU (1) | AU643911B2 (fr) |
CA (1) | CA2098568C (fr) |
CZ (1) | CZ289299B6 (fr) |
DE (1) | DE69229916T2 (fr) |
DK (1) | DK0605638T3 (fr) |
ES (1) | ES2137951T3 (fr) |
FI (1) | FI109796B (fr) |
HU (1) | HU225914B1 (fr) |
IL (1) | IL103192A (fr) |
MX (1) | MX9205370A (fr) |
MY (1) | MY128481A (fr) |
NO (1) | NO305120B1 (fr) |
NZ (1) | NZ244458A (fr) |
PH (1) | PH30213A (fr) |
PT (1) | PT100884B (fr) |
RU (1) | RU2098413C1 (fr) |
TW (1) | TW368502B (fr) |
UA (1) | UA41287C2 (fr) |
WO (1) | WO1993006094A1 (fr) |
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ZA926829B (en) * | 1991-09-23 | 1993-03-15 | Univ Florida State | Novel substituted taxanes and pharmaceutical compositions containing them. |
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AU6367994A (en) * | 1993-03-22 | 1994-10-11 | Florida State University | Taxanes having alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing same |
FR2718137B1 (fr) * | 1994-04-05 | 1996-04-26 | Rhone Poulenc Rorer Sa | Procédé de préparation de trialcoylsilyl-7 baccatine III. |
JP2001524067A (ja) * | 1995-09-13 | 2001-11-27 | フロリダ・ステイト・ユニバーシティ | 放射線感作性タキサン類およびその医薬製剤 |
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CN101289432B (zh) * | 2007-04-20 | 2010-12-15 | 上海天伟生物制药有限公司 | 异丝氨酸酯衍生物及其制备方法 |
KR101096282B1 (ko) | 2009-04-24 | 2011-12-20 | 주식회사 삼양제넥스 | 탁산 유도체를 제조하는 방법 |
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